EP0172141A1 - Substituted pyridazinones, method for their preparation, pharmaceutical preparation containing these compounds and their use - Google Patents

Abstract

The present invention relates to novel substituted pyridazinones of the general formula I <IMAGE> (I) wherein R is a halogen atom, a lower alkyl or lower alkoxy group, the nitro, hydroxyl, cyano, carboxyl, lower alkoxycarbonyl or carbamoyl group or the trifluoromethyl group, and Z is hydrogen or an acyl group, and the salts and tautomeric forms thereof, which have a marked antithrombotic action, to the production of these novel compounds, to pharmaceutical preparations containing them, and to their use.

Description

The present invention relates to new substituted pyridazinones, in particular 5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinones, their preparation, and pharmaceutical preparations containing these new compounds, and also their use.

worin R ein Halogenatom, eine Niederalkyl-, Niederalkoxy-, die Nitro-, Hydroxy-, Cyano-, Carboxy-, Niederalkoxycarbonyl-, Carbamoyl- oder die Trifluormethylgruppe bedeutet, und Z Wasserstoff oder eine Acylgruppe bedeutet, ihre Salze und ihre tautomeren Formen eine ausgeprägte antithrombotische Wirkung aufweisen.Surprisingly, it has now been found that the new compounds of the general formula I

wherein R represents a halogen atom, a lower alkyl, lower alkoxy, the nitro, hydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl or the trifluoromethyl group, and Z represents hydrogen or an acyl group, their salts and their tautomeric forms have pronounced antithrombotic effects.

The term "lower" in the organic radicals or compounds mentioned above or below defines those having at most 7, preferably 4, in particular 1 or 2, carbon atoms.

R as lower alkyl is e.g. Ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl and especially methyl; as lower alkoxy, e.g. Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and especially methoxy; and as halogen bromine, iodine, especially fluorine or especially chlorine.

R as lower alkoxycarbonyl is e.g. the methoxycarbonyl or ethoxycarbonyl group.

Y as acyl is the residue of an organic carboxylic acid, e.g. Lower alkanoyl, e.g. Acetyl, propionyl or butyryl, halogeno lower alkanoyl such as e.g. Haloacetyl, e.g. Chloroacetyl or aroyl, e.g. Benzoyl. The phenyl radical in the benzoyl group can optionally be substituted one or more times by halogen, lower alkyl, lower alkoxy, hydroxy, nitro, carboxy or also by trifluoromethyl.

The compounds of formula I have valuable pharmacological properties. For example, they have pronounced antithrombotic activity. In guinea pigs, for example, this can be based on the inhibition of thrombocytopenia after induction by ADP (Thromboembolism, Edited by JR Mitchell & JG Doment, Academic Press, (1977), p. 36) in the dose range of approximately 30 to 300 mg / kg po, on the basis of Forssman reaction (Thrombosis, Haemostasis 42, 100 (1979)) in the dose range from about 100 to 300 mg / kg po, and based on the inhibition of thrombosis forming on a cotton thread in an extracorporeal shunt in the rat (method analogous to Brit. J Pharmacol., 73, 219 P (1981)) in the dose range of about 5 to 50 mg / kg po, and on the basis of the inhibition of platelet aggregation induced ex vivo by collagen or arachindonic acid after previous oral application of the active ingredient in doses of 5 to 100 mg / kg can be demonstrated. The compounds of the general formula I are accordingly particularly suitable for the treatment of thrombotic diseases and can be used as active ingredients in antithrombotic medicaments.

The invention relates primarily to compounds in which R is a halogen atom, the cyano, hydroxyl, carboxy, lower alkyl, lower alkoxy or also the trifluoromethyl group and Z is hydrogen or lower alkanoyl, their salts and their tautomers To form.

Of particular interest in this invention are compounds in which R is a halogen atom, in particular chlorine, a lower alkyl group, in particular methyl or else the cyano group and Z is hydrogen or also lower alkanoyl, in particular acetyl, and their tautomeric forms.

The compounds of the formula I and their tautomeric forms described in the examples should be mentioned in particular.

The new pyridazinones of the formula I are prepared by methods known per se.

oder ein reaktionsfähiges Derivat einer solchen Ketocarbonsäure, worin R und Z die oben angegebene Bedeutung haben, mit Hydrazin umsetzt. Vorzugsweise verwendet man das in Hydratform vorliegende Hydrazinhydrat, welches im Ueberschuss verwendet auch gleichzeitig als Lösungsmittel dienen kann. Zweckmässiger ist es jedoch, ein zusätzliches inertes Lösungsmittel zuzusetzen. Als inerte Lösungsmittel eignen sich vorzugsweise Alkohole wie z.B. Methanol, Aethanol, Isopropanol, n-Butanol, Isoamylalkohol, Glykole und deren Aether wie Aethylenglykol, Diäthylenglykol, Aethylenglykolmonomethyl- oder -monoäthyläther (Methylglykol oder Aethylglykol),So you can get the new compounds of formula I by using a ketocarboxylic acid of formula II

or reacting a reactive derivative of such a ketocarboxylic acid, in which R and Z have the meaning given above, with hydrazine. The hydrazine hydrate present in hydrate form is preferably used, which in excess can also serve as a solvent at the same time. However, it is more expedient to add an additional inert solvent. Suitable inert solvents are preferably alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamyl alcohol, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol),

furthermore ethers, in particular water-soluble ethers such as tetrahydrofuran, dioxane or ethylene glycol dimethyl ether (diglyme); also water, and mixtures of these solvents with one another, in particular mixtures with water, e.g. aqueous ethanol. The reaction temperatures are advantageously between about 20 and about 200 ° C, preferably between 60 and 80 ° C.

zum Umsatz mit Hydrazin oder einem Hydrazinhydrat.Suitable reactive derivatives of the ketocarboxylic acid of the formula II are, for example, the esters, in particular lower alkyl esters, such as, for example, methyl or also ethyl esters. Furthermore, the acid amides and acid halides of the acids of the formula II, in particular the acid chlorides or acid bromides, can also be used. Lactones of the formula IIa are particularly suitable

for sales with hydrazine or a hydrazine hydrate.

worin R₁ die Bedeutung des Restes

hat.Further suitable reactive derivatives of the carboxylic acid of the formula II can be formed in situ during the reaction. These include, for example, the hydrazones of the formula R ₁ -C (= N-NH ₂ ) -CH - (- CH ₂ -0Z) -CH ₂ -COOH, the hydrazides of the formula R ₁ -CO-CH (-CH ₂ -OZ ) -CH ₂ -CO-NH-NH ₂ and the hydrazones of the hydrazides of the formula

wherein R _{1 is} the meaning of the rest

Has.

The starting materials formed in situ are prepared from the ketocarboxylic acids of the formula II and are not isolated from the reaction mixture, but are further converted to the compounds of the formula I.

The compounds of formula I can also be obtained by using compounds of formula III

wherein R and Z have the meanings given under formula I, and Y represents a group which can be split off together with hydrogen, is reacted with morpholine. The morpholine used is advantageously used in excess as a free base, but can also be in the form of an acid addition salt, for example as a hydrohalide, e.g. Hydrochloride.

If only a slight excess of the morpholine is used as the free base or if the morpholine is used as the acid addition salt, it is expedient to add a stoichiometrically equivalent amount, e.g. of a tertiary alkylamine, such as triethylamine or N-ethyldiisopropylamine, is also added.

The described reaction of compounds of formula III with morpholine is optionally carried out in the presence of a solvent, preferably an aprotic solvent. Examples of preferred solvents are ethers, such as e.g. Diethyl ether and tetrahydrofuran, especially aliphatic ketones and esters, e.g. Acetone, methyl ethyl ketone and ethyl acetate, aromatic hydrocarbons such as e.g. Benzene, toluene or xylene, and acetonitrile. The reaction can particularly preferably be carried out in diethyl ether or acetonitrile.

The reactions can be carried out at a temperature between 0-150 ° C., but preferably between room temperature and the reflux temperature of the reaction mixture.

A group Y which can be split off together with hydrogen is e.g. primarily a free or preferably etherified mercapto group, furthermore an optionally reactive, functionally modified hydroxy group or the nitroamino group. An etherified mercapto group is primarily a mercapto group etherified by an optionally substituted hydrocarbon radical, in particular an aliphatic character. It primarily represents lower alkylthio, e.g. Methylthio, ethylthio or butylthio, also phenylthio or phenyl-lower alkylthio, e.g. Benzylthio. An optionally reactive, functional modified hydroxy group is a free and, inter alia, a corresponding esterified hydroxy group. One such is Halogen, e.g. Chlorine or bromine, or lower alkylsulfonyloxy, e.g. Methanesulfonyloxy.

Preferably Y is a halogen atom, such as e.g. Chlorine or bromine.

mit einem Diäthylätherderivat der Formel V

worin X eine zusammen mit Wasserstoff abspaltbare Gruppe bedeutet und R und Z die oben angegebenen Bedeutungen haben, umsetzt.Compounds of general formula I can also be prepared by using a compound of formula IV

with a diethyl ether derivative of formula V

in which X denotes a group which can be split off together with hydrogen and R and Z have the meanings indicated above.

The reaction of a compound of formula IV with a compound of formula V is preferably carried out in the presence of an organic base such as e.g. a tertiary alkylamine such as triethylamine or N-ethyldiisopropylamine.

The described reaction of compounds of formula IV with a compound of formula V is optionally carried out in the presence of a solvent, preferably a polar solvent, such as e.g. Dimethylformamide.

The reactions can be carried out at a temperature between 0-200 ° C., but preferably between room temperature and the reflux temperature of the reaction mixture.

A group X which can be split off together with hydrogen has already been defined above for the symbol Y under formula III.

As a group which can be split off together with hydrogen, X preferably denotes a halogen atom, for example chlorine or bromine.

worin X_l ^e ein Anion einer Mineralsäure bedeutet, beispielsweise in Gegenwart von Kupfer oder eines Kupfer-I-salzes, beispielsweise eines Halogenids oder Cyanids erhitzt. Ein Anion einer Mineralsäure ist beispielsweise das Anion einer Halogenwasserstoffsäure. Im Falle der Einführung von R . Fluor ist X₁⊖ ein Fluorid- oder Tetrafluorboratanion. Die Erhitzung einer Verbindung der Formel VI erfolgt für den Fall, dass X₁ ein Fluorid- oder Tetrafluorboratanion ist, in Flusssäure oder in Tetrafluorborsäure. Bei der Einführung einer Cyanogruppe setzt man beispielsweise das Diazoniumsalz der Formel VI mit Kupfer-I-cyanid, das in Kaliumcyanid komplex gelöst ist, um. Beispielsweise setzt man ein Diazoniumsalz der Formel VI mit einem Gemenge aus Kaliumcyanid und Kupfer-I-sulfat um. Die Freisetzung des Diazoniumsalzes erfolgt thermisch bei Temperaturen zwischen 30-150°C, vorzugsweise zwischen 30-40° bei Vorliegen eines Diazoniumfluorids und zwischen 100-150°C bei Vorliegen eines Diazoniumtetrafluorborates.In a further process, compounds of the formula I in which R is a halogen atom or the cyano group can be prepared by using a compound of the formula VI

wherein X _l ^{e is} an anion of a mineral acid, for example heated in the presence of copper or a copper I salt, for example a halide or cyanide. An anion of a mineral acid is, for example, the anion of a hydrohalic acid. In the case of the introduction of R. Fluorine is X ₁ ⊖ a fluoride or tetrafluoroborate anion. The heating of a compound of the formula VI takes place in the case where X _{1 is} a fluoride or tetrafluoroborate anion, in Hydrofluoric acid or in tetrafluoroboric acid. When a cyano group is introduced, for example, the diazonium salt of the formula VI is reacted with copper-I-cyanide, which is complexly dissolved in potassium cyanide. For example, a diazonium salt of the formula VI is reacted with a mixture of potassium cyanide and copper I-sulfate. The diazonium salt is released thermally at temperatures between 30-150 ° C, preferably between 30-40 ° C in the presence of a diazonium fluoride and between 100-150 ° C in the presence of a diazonium tetrafluoroborate.

Aromatic amines are diazotized, for example, with an alkali metal such as sodium nitrite, preferably with the aid of dry sodium nitrite. The diazotization is carried out, for example, at a temperature between -10 ° and + 10 ° C, preferably at a temperature between 0-5 ° C. Reaction with a mineral acid gives compounds of the formula VI in which X _{1 is} the anion of a mineral acid.

halogeniert.According to a further process, compounds of the formula I in which R is a halogen atom can be prepared by reacting compounds of the formula VII

halogenated.

The halogenation can be carried out on the one hand using halogen, preferably in the presence of a Lewis acid, for example an iron III, aluminum, antimony III or tin IV halide. On the other hand, the halogenation can also be carried out with the aid of a halogen transfer agent, for example in the presence of a heavy metal, for example iron, or using a halogenating agent, for example hydrogen chloride in the presence of an oxidizing agent such as hydrogen peroxide, or an alkali metal, for example sodium chlorate, a nitrosyl halide, for example nitrosyl chloride or bromide, or an N-halo imide, for example bromosuccinimide or phthalimide.

The direct introduction of an iodine atom takes place when using hydrogen iodide in the presence of an oxidizing agent, for example in the presence of nitric acid or mercury oxide.

Depending on the importance of the halogen atom, the halogenations mentioned are carried out at temperatures between -10 ° C. and the reflux temperature of the reaction mixture, preferably at temperatures between -5 ° and 30 ° C.

in der R' die Bedeutung von R hat oder eine leicht solvolysierbare oder hydrogenolysierbare Aethergruppe oder Acyloxygruppe bedeutet und -OZ' eine leicht solvolysierbare oder hydrogenolysierbare Aether- oder Acyloxygruppe bedeutet, solvolysiert oder hydrogenolysiert.Compounds of the formula I in which R has the meanings given under formula I and Z is hydrogen can also be obtained by using a compound of the formula VIII

in which R 'has the meaning of R or denotes an easily solvolysable or hydrogenolyzable ether group or acyloxy group and -OZ' denotes an easily solvolysable or hydrogenolyzable ether or acyloxy group, solvolysed or hydrogenolyzed.

An easily solvolysable or also hydrogenolyzable ether or acyloxy group is e.g. an ether or acyloxy group which can be split off by solvolysis, including hydrolysis, acidolysis or alcoholysis or by means of reduction, including hydrogenolysis.

An acyloxy group R 'or -OZ' which can be split off by solvolysis is, for example, an acyloxy group in which the acyl part is the remainder of an organic carboxylic acid, e.g. Lower alkanoyl such as acetyl, halogen lower alkanoyl such as haloacetyl e.g. Chloroacetyl, or carbamoyl, or aroyl, such as benzoyl, furthermore the acyl radical the remainder of a half ester of carbonic acid, such as lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halogeno lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, e.g. Benzyloxycarbonyl or diphenylmethoxycarbonyl or aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, in which substituents of the phenyl part, e.g. Lower alkyl or lower alkoxy, e.g. May be methyl or methoxy, and primarily mean trityl or an organosilyl radical, in particular trimethylsilyl.

A solvolytically removable ether group is e.g. Lower alkoxy, e.g. methoxy or ethoxy, or a 1-phenyl-lower alkoxy group, e.g. Benzyloxy. These residues can be replaced by lower alkoxy, e.g. Methoxy or ethoxy, or also lower alkoxyethoxy, e.g. Methoxyethoxy may be substituted.

Benzyloxy radicals as cleavable ether groups can optionally be substituted by one or more substituents, e.g. Lower alkyl, for example methyl, ethyl, isopropyl or n-propyl, halogen, for example chlorine or bromine, or also lower alkoxy, such as e.g. Methoxy or ethoxy. These substituents are preferably in the ortho or also in the para position.

Likewise solvolytically, in particular hydrolytically or alcoholically, cleavable in acid medium are aliphatic ether groups, such as ethoxymethoxy, butoxymethoxy or 1-ethoxyethoxy, substituted in the a position by an ether group, and in particular Analogous cyclic radicals, for example 1-oxacycloalkan-2-yloxy groups, especially tetrahydropyran-2-yloxy, and also for example 4-methoxytetrahydropyran-4-yloxy.

If the solvolysis of the ether or acyloxy groups R 'and / or · Q2' is carried out hydrolytically, depending on the nature of the groups which can be split off, this is carried out in the presence of an organic acid, such as p-toluenesulfonic acid or a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate, or in the presence of ammonia or an amine such as isopropylamine, or hydrazine hydrate. If the solvolysis is carried out using one of the abovementioned acids in an alcohol, for example using p-toluenesulfonic acid in ethyl alcohol, the solvolysis is carried out alcoholically.

Ether groups, e.g. Lower alkoxy groups, especially methoxy or ethoxy, can be in solution or melt using a metal halide such as e.g. Aluminum or boron halide, for example aluminum trichloride, aluminum tribromide, boron trichloride, or also boron tribromide, can be split off. Suitable solvents are, for example, benzene, nitrobenzene or ethylene chloride. (See Jour. Chem. Soc. (1961), 1008; Ber. (1943), 76B, 900; Jour. Org. Chem. (1962), 27, 2037; Ber. (1960), 92, 2761; Jour Am. Chem. Soc. (1968), 24, 2289; Tetr. Lett. (1966), 4155).

Acylolytically cleavable are acyloxy groups in which the acyl part is an acyl radical of half-esters of carbonic acid, such as tert-lower alkoxycarbonyl, or optionally substituted diphenylmethoxycarbonyl. In addition, ether groups such as tert-lower alkoxy groups can also be split off acidolytically. The acidolytic cleavage can be carried out by treatment with suitable strong organic carboxylic acids, such as optionally substituted by halogen, in particular fluorine, lower alkanoic acids, primarily trifluoroacetic acid (if necessary in the presence of an activating agent such as anisole), and with formic acid. The above If not already mentioned, reactions are carried out in the presence of a solvent or solvent mixture, suitable reactants also being able to serve as such.

An ether group which can be split off by reduction, in particular by hydrogenolysis, is primarily an a-aryl-lower alkyl group, such as an optionally substituted 1-phenyl-lower alkyl group, in which lower alkyl has up to 7 carbon atoms and in which substituents, in particular of the phenyl part, e.g. Lower alkyl or lower alkoxy each having up to 7 carbon atoms, e.g. May be methyl or methoxy, and especially benzyl.

The reductive cleavage of the ether groups can in particular e.g. by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. Nickel, platinum or palladium, but also a rhodium or ruthenium catalyst, or one works with a hydride reducing agent, e.g. Lithium aluminum hydride.

Acyloxy radicals which can be split off by hydrogenolysis are understood to mean those groups which are split off when treated with a chemical reducing agent (in particular with a reducing metal or a reducing metal compound). Such residues are in particular 2-halogeno lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, which, for example, with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as chromium (II) salt, for example ⁼ chloride or acetate, are customary in the presence of an organic carboxylic acid such as formic acid or acetic acid.

The above reduction reactions are carried out in a manner known per se, usually in the presence of an inert solvent and, if necessary, with cooling or heating, e.g. in a temperature range from about -20 ° to about 150 ° C, and / or in a closed vessel under pressure.

Depending on the ether or acyloxy group present, the most gentle of the solvolysis or hydrogenolysis methods described is preferably selected in order to avoid changes to the pyridazinone structure.

In the compounds of formula I obtained, substituents can be introduced, modified or eliminated within the scope of the definition of the end products.

For example, compounds of the formula I obtained in which R denotes a hydroxyl group can be converted in a manner known per se by transesterification or etherification into compounds of the formula I in which R denotes a halogen atom or a methoxy group.

The processes described can be carried out in the usual manner at room temperature, with cooling or heating, at atmospheric pressure or elevated pressure and, if necessary, in the presence or absence of a diluent, catalyst or condensing agent. If necessary, the reactions can also be carried out in the atmosphere of an inert gas, e.g. Nitrogen.

The starting materials are known or, if they are new, can be prepared by methods known per se. Where it proves to be expedient, the starting products used have already been described following the process described.

Ketocarboxylic acids of the formula II can be prepared by methods known per se, for example for compounds of the formula II in which R denotes a halogen atom or also a cyano group, by halogenation or introduction of a cyano group in a compound of the formula X

nach den oben beschriebenen Methoden, die in analoger Weise ausgeführt werden.

according to the methods described above, which are carried out in an analogous manner.

The lactones of the formula IIa used as derivatives can be obtained from the 3- (4-morpholino-benzoyl) propionic acid correspondingly substituted by the substituent R by conversion with formaldehyde according to "Synthesis", Georg Thieme Verlag, (October 1980), p. 825 Received -827.

Compounds of the general formula III are known or can be prepared according to the method described by JD Albright et al, J. Het. Chem. 15, 881 (1978) method can be obtained from the corresponding ketocarboxylic acid by reaction with hydrazine. The starting compounds of the general formula IV can also be obtained in an analogous manner from the corresponding aminoketocarboxylic acids. The starting compounds of the general formula V are also known and can be obtained, for example, from the corresponding dihydroxydiethyl ethers by esterification with an acid, for example hydrohalic acid. Diethylither derivatives of the formula V can also be obtained from correspondingly substituted alcohols of the formula OH-CH ₂ -CH ₂ -X by etherification.

The starting compound of formula VI can be prepared from the corresponding nitro compound by reduction into the amino compound and subsequent diazotization.

Compounds of the general formulas VIII and IX can be obtained from the corresponding ketocarboxylic acids by reaction with hydrazine by the method described in the first process.

The invention also relates to those embodiments of a process in which a process is terminated at any stage or in which one starts from a compound obtainable as an intermediate at any stage and carries out the missing steps, or a starting material under the reaction forms conditions or optionally used in the form of a salt. The invention also includes new intermediates resulting therefrom.

The invention also encompasses therapeutic compositions which consist of an antithrombotically active portion of the compounds of the formula I and a pharmacologically acceptable solid carrier or liquid diluent.

A compound of formula I obtained, in which R represents a carboxy group, can be prepared in a manner known per se, e.g. by reaction with an approximately stoichiometric amount of a suitable salt-forming agent such as ammonia, an amine or an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate. Ammonium or metal salts thus obtainable can be treated by treatment with an acid, e.g. Convert hydrochloric acid, sulfuric acid or acetic acid into the free acid until the necessary pH value is reached.

The acid addition salts of the new compounds can be converted into the free compounds in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids.

The pharmaceutical preparations according to the invention contain at least one compound of the formula I as active ingredient together with a customary pharmaceutical carrier. The type of carrier largely depends on the area of application. The pharmaceutical compositions according to the invention which contain compounds of the formula I as active compounds can be administered orally, parenterally or rectally.

For oral treatment of thrombosis, solid unit dosage forms such as tablets, coated tablets and capsules are particularly suitable, which preferably contain between 10 and 90% of an active ingredient of the general contain my formula I to allow the administration of daily doses between 1.0 to 1000 mg / kg, preferably between 2 and 100 mg / kg, in particular between 5 to 10 mg / kg, to warm-blooded animals of approximately 70 kg body weight. To produce tablets and dragee cores, the compounds of the formula I are combined with solid, powdery carriers, such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of lubricants, such as magnesium or calcium stearate, or polyethylene glycols of suitable molecular weight. Drage cores are then coated, for example, with concentrated sugar solutions, which may, for example, also contain arabic gum, talc and / or titanium dioxide, or with a lacquer dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, for example for labeling different doses of active ingredient. Soft gelatin capsules and other closed capsules consist, for example, of a mixture of gelatin and glycerin and can contain, for example, mixtures of a compound of the formula 1 with polyethylene glycol. Plug-in capsules contain, for example, granules of an active ingredient with solid, powdery carriers, such as lactose, sucrose, sorbitol, mannitol; Starches such as potato starch, corn starch or amylopectin, cellulose derivatives and magnesium stearate or stearic acid.

Can unit forms for rectal use include e.g. Suppositories, which consist of a combination of an active ingredient with a suppository base based on natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capsules, which contain a combination of the active ingredient with polyethylene glycols.

For liquids for oral ingestion, such as syrups and elixirs, the concentration of the active ingredient is chosen such that a single dose can easily be measured, e.g. as the content of a teaspoon or a measuring spoon of e.g. 5 ml, or as a multiple of these volumes.

The following examples a) to e) are intended to explain the production of some typical application forms, but in no way represent the only embodiments of such.

• a) 100.0 g of active ingredient are mixed with 610.0 g lactose and 442.0 g potato starch, the mixture is moistened with an alcoholic solution of 8 g gelatin and granulated through a sieve. After drying, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets, each weighing 125 mg and 10 mg of active ingredient, which, if desired, with partial notches for fine adjustment the dosage can be provided.
• b) Granules are prepared from 100.0 g of active ingredient, 379.0 g of lactose and the alcoholic solution of 6.0 g of gelatin, which after drying are mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talc, 60 , 0 g potato starch and 5.0 g magnesium stearate are mixed and pressed to 10,000 dragee kernels. These are then crystallized with a concentrated syrup of 533.5 g. Sucrose, 20.0 g shellac, 75.0 g arabic gum, 250.0 g talc, 20.0 g colloidal silicon dioxide and 1.5 g dye coated and dried. The dragees obtained each weigh 150 mg and contain 10 mg of active ingredient each.
• c) 10.0 g of active ingredient and 1990 g of finely grated suppository base (e.g. cocoa butter) are mixed thoroughly and then melted. 1000 supositories of 2.0 g are poured from the melt, which is kept homogeneous by stirring. They each contain 25 mg of active ingredient.
• d) To prepare a syrup with an active substance content of 0.25%, dissolve in 3 liters of dist. Water 1.5 liters of glycerol, 42 g of methyl p-hydroxybenzoate, 18 g of n-propyl p-hydroxybenzoate and 25.0 g of active ingredient with gentle heating, adds 4 liters of 70% sorbitol solution, 1000 g of crystals. Sucrose, 350 g glucose and a flavoring e.g. 250 g of "Orange Peel Soluble Fluid" from Eli Lilly and Co., Indianapolis, or 5 g of natural lemon flavor and 5 g of "half and half" essence, both from the company Haarmann and Reimer, Holzminden, Germany, are filtered Solution and supplement the filtrate with dist. Water to 10 liters.
• e) To prepare a drip solution with an active ingredient content of 1.5%, 150.0 g of active ingredient and 30 g of sodium cyclamate are dissolved in a mixture of 4 liters of ethanol (96%) and 1 liter of propylene glycol. On the other hand, mix 3.5 liters of 70% sorbitol solution with 1 liter of water and add the mixture to the above active ingredient solution. A flavoring, e.g. 5 g cough drop flavor or 30 g grapefruit essence, both added by Haarmann and Reimer, Holzminden, Germany, mixed well, filtered and with distilled water. Add water to 10 liters.

The following examples illustrate the preparation of the new compounds of the formula I, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Celsius.

Example I: 11.2 g of 4- (3-cyano-4-morpholino-benzoyl) butyrolactone are kept under reflux for 16 hours together with 2.55 ml of hydrazine hydrate and 170 ml of ethanol. Then 29.7 ml of glacial acetic acid are added and the mixture is stirred under reflux for a further 5 hours. The reaction mixture is then cooled to room temperature with stirring and the crystals which precipitate are filtered off and washed with a little ethanol and diethyl ether. 5.6 g of 6- (3-cyano-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone of mp 217-218 ° are obtained.

• 10 g 3-(3-cyano-4-morpholino-benzoyl)-propionsäure werden zusammen mit 2,98 g 35 %iger Formaldehydlösung und 76,4 ml 0,5 N Natronlauge 16 Stunden bei Raumtemperatur gerührt. Danach wird das Reaktionsgemisch unter Rühren und Kühlen mit Eiswasser mit konzentrierter Salzsäure sauer gestellt und nochmals 16 Stunden bei Raumtemperatur gerührt. Es wird Aethylacetat zugegeben, bis sich zwei klare Phasen bilden. Die wässrige Phase wird abgetrennt und mit Aethylacetat extrahiert. Die organischen Phasen werden zweimal mit 2N Sodalösung, mit Wasser und mit Sole gewaschen, über Natriumsulfat getrocknet und eingedampft. Das als öligen Rückstand erhaltene 4-(3-Cyano-4-morpholino-benzoyl)-butyrolacton wird direkt in der Folgestufe eingesetzt.

The 4- (3-cyano-4-morpholino-benzoyl) butyrolactone used as the starting material is prepared as follows:

• 10 g of 3- (3-cyano-4-morpholino-benzoyl) propionic acid are stirred together with 2.98 g of 35% formaldehyde solution and 76.4 ml of 0.5 N sodium hydroxide solution at room temperature for 16 hours. The reaction mixture is then acidified with concentrated hydrochloric acid while stirring and cooling with ice water and stirred again at room temperature for 16 hours. Ethyl acetate is added until two clear phases form. The aqueous phase is separated off and extracted with ethyl acetate. The organic phases are washed twice with 2N sodium carbonate solution, with water and with brine, dried over sodium sulfate and evaporated. The 4- (3-cyano-4-morpholino-benzoyl) butyrolactone obtained as an oily residue is used directly in the next stage.

Example 2: Analogously to Example 1, one obtains:

From the 3- (3-chloro-4-morpholino-benzoyl) propionic acid the 6- (3-chloro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) pyridazinone of mp. 176-178 °.

From the 3- (3-nitro-4-morpholino-benzoyl) propionic acid the 6- (3-nitro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) pyridazinone of mp. 216-217 °.

Example 3: 1 g of 6- (3-cyano-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone together with 0.3 ml of acetic anhydride, 0.66 ml of triethylamine , 20 ml of chloroform and 20 ml of dimethylformamide are stirred at 70 ° for 25 hours, 0.3 ml of acetic anhydride being added after 5 and 20 hours. The reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel in the ethyl acetate: methanol - 99: 1 system. 1 g of 6- (3-cyano-4-morpholino-phenyl) -5-acetoxymethyl-4,5-dihydro-3 (2H) -pyridazinone is obtained as an amorphous solid (foam) with a melting point of 60-69 ° (R. _f in the system ethyl acetate: methanol - 9: 1 is 0.48).

Example 4: 45 g of 3-chloro-4-amino-benzoyl-propionic acid are stirred together with 50 ml of 35% formaldehyde solution and 440 ml of 0.5 N sodium hydroxide solution at room temperature for 17 hours.

The reaction mixture is adjusted to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phases are washed with water, dried over sodium sulfate and evaporated. The residue, 3- (3-chloro-aminobenzoyl) -3-hydroxymethyl-propionic acid is reacted directly, unpurified, by refluxing it together with 1600 ml of ethanol and 18 ml of hydrazine hydrate for 5 hours. The reaction mixture is evaporated and the residue is partitioned between 4N hydrochloric acid and ethyl acetate. The aqueous phases are made basic with 2N sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate extracts are washed twice more with 2N sodium carbonate solution and with water, dried over sodium sulfate and evaporated. The crude 6- (3-chloro-4-aminophenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone, which together with 25 g of β, β-dibromo-diethyl ether, and 37 ml of diisopropylethylamine in 150 ml of dimethylformamide is heated under reflux for 18 hours. The reaction mixture is evaporated on a rotary evaporator in a high vacuum. The residue is taken up in ethyl acetate and washed several times with 1N hydrochloric acid and water. The organic phase is dried over sodium sulfate and concentrated. The 6- (3-chloro-4-morpholinophenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone crystallizes out. The mp. Is 172-173 ".

Example 5: 26.3 g of p-morpholino-benzoyl-propionic acid are stirred together with 25 ml of 35% formaldehyde solution and 220 ml of 0.5N sodium hydroxide solution at room temperature for 18 hours.

The reaction mixture is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phases are washed with water, dried over sodium sulfate and evaporated. The residue, the crude 3- (p-morpholino-benzoyl), 3-hydroxymethylpropionic acid together with 9 ml of hydrazine hydrate and 800 ml Ethanol heated to reflux for 5 hours. The reaction mixture is then evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and the organic phases are washed several times with 2N sodium carbonate and water, then dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with a mixture of ethyl acetate: methanol = 9: 1.

The 6- (4-morpholino-phenyl) -5-hydroxymethyl-4,5-di-hydro-3- (2H) -pyridazinone thus obtained is dissolved in a mixture of 16 ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid and with stirring -10 ° with the solution of 1.8 g of sodium chlorate in 2 ml of water. The mixture is further stirred at 0 ° for 30 minutes and at room temperature for 30 minutes and then poured onto 400 ml of ice water. The resulting suspension is adjusted to pH 6 with concentrated NaOH and extracted with ethyl acetate. The ethyl acetate extracts are washed with 1N sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated. The residue is purified on silica gel with a mixture of ethyl acetate: methanol - 9: 1. By recrystallizing the corresponding fractions from ethyl acetate, the 6- (3-chloro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone is obtained. Mp 173-175 °.

Example 6: 10 g of 6- (3-nitro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone are mixed with 1 g of catalyst palladium on carbon in 200 ml of ethanol at room temperature and Low pressure hydrogenated.

For working up, the catalyst is slurried in 1N hydrochloric acid, suction filtered and washed with 1N hydrochloric acid. The filtrate is adjusted to pH 6 with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and evaporated.

The residue, the crude 6- (3-amino-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone is dissolved in a mixture of 90 ml of concentrated hydrochloric acid and 90 ml of water and at 0-5 ° below Stirring with the solution of 2.9 g of sodium nitrite in 10 ml of water is diazotized, the excess nitrite being destroyed after 15 minutes with urea. The solution of 18 ml of copper (I) chloride in a mixture of 90 ml of water and 90 ml of concentrated hydrochloric acid is then added rapidly. When the addition is complete, the reaction mixture is stirred for 3 hours at room temperature and for a further 2 hours at 40 °, then adjusted to pH 10 and extracted with ethyl acetate. The ethyl acetate phases are washed with water and brine, dried over sodium sulfate and evaporated. Purification of the residue on silica gel with a mixture of ethyl acetate: methanol - 9: 1 and recrystallization from ethyl acetate gives the 6- (3-chloro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 ( 2H) pyridazinone, mp 174-176 °.

Example 7: 25 g of 3-nitro-4-chloro-benzoyl-propionic acid are stirred together with 25 ml of 35X formaldehyde solution and 220 ml of 0.5N sodium hydroxide solution at room temperature for 16 hours. The reaction mixture is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phases are washed with water, dried over sodium sulfate and evaporated. The 3- (3-nitro-4-chloro-benzoyl) -3-hydroxymethyl-propionic acid obtained as residue is boiled under reflux for 5 hours together with 9 ml of hydrazine hydrate and 800 ml of ethanol. The reaction mixture is then evaporated and the residue is stirred together with 170 ml of dimethyl sulfoxide, 10 ml of morpholine and 15 ml of diisopropylethylamine at 80 ° for 3 hours. The reaction mixture is then evaporated on a rotary evaporator under high vacuum and the residue is refluxed in 90 ml of methylene chloride for 30 minutes. By cooling to 0 °, the 6- (3-nitro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone crystallizes out with stirring, mp. 210-213 °.

Example 8: The solution of 5 g of 3- (3-cyano-4-morpholino-benzoyl) propionic acid in 50 ml of dimethylformamide is added dropwise to a solution of 1.66 ml of sodium hydride dispersion in 50 ml of dimethylformamide. The reaction mixture is stirred at 70 ° for 30 minutes and then dropwise at -70 ^* with 7.2 ml of benzyl chloromethyl ether with stirring transferred. The mixture is stirred for 1 hour at -70 ° and 16 hours at room temperature. 30 ml of water, 10 ml of 2N hydrochloric acid and 50 ml of water are then added in succession, the mixture is extracted with ether and, after washing with water and drying over sodium sulfate, the ether phases are evaporated.

The residue is stirred with 4 ml of hydrazine hydrate and 200 ml of 50X acetic acid together at 100 ° for 2 hours and at room temperature for 16 hours. The mixture is evaporated on a rotary evaporator and the residue is taken up in ethyl acetate. The organic phases are washed with water, 1N sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated.

The residue is obtained by chromatography on silica gel with a mixture of toluene: ethyl acetate. 1: 1 the 6- (3-cyano-4-morpholino-phenyl) -5-benzyloxymethyl-4,5-dihydro-3 (2H) -pyridazinone, mp. 156-167 °.

1 g of 6- (3-cyano-4-morpholino-phenyl) -5-benzyloxymethyl-4,5-dihydro-3 (2H) -pyridazinone are hydrogenated in 100 ml of ethanol with 0.3 g of palladium-on-carbon catalyst. The catalyst is filtered off and the filtrate is evaporated. The residue is refluxed in 8 ml of methylene chloride for 30 minutes and cooled to 0 °. The 6- (3-cyano-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone crystallizes out with stirring. After recrystallization from ethanol-dimethylformamide, the mp. Is 219-221 °.

Example 9: 86.5 g of 3- (3-cyano-4-morpholino-benzoyl) propionic acid are stirred together with 79 ml of 35% formaldehyde solution and 660 ml of 0.5N sodium hydroxide solution at room temperature for 17 hours. The pH is then adjusted to 3 with 160 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The organic phases are dried with sodium sulfate and evaporated. The residue is stirred together with 28 ml of hydrazine hydrate and 2850 ml of ethanol at reflux for 5 hours and then evaporated on a rotary evaporator. The residue is suspended in 900 ml of methylene chloride and 30 minutes heated to reflux. After cooling to 0 °, the product crystallizes out. The 6- (3-cyano-4-morpholino-phenyl -) - 5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone of mp. 213-215 ° is obtained. By recrystallization from 400 ml of methylene chloride with 400 ml of ethanol, the mp increases to 221-222 °.

Claims (22)

1. Pyridazinones of the general formula I

wherein R represents a halogen atom, a lower alkyl, lower alkoxy, the nitro, hydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl or the trifluoromethyl group, and Z represents hydrogen or an acyl group, their salts and their tautomeric forms. 2. pyridazinones of the general formula I according to claim 1, wherein R is a halogen atom, the cyano, hydroxyl, carboxy, lower alkyl, lower alkoxy or also the trifluoromethyl group and Z has the meaning of hydrogen or lower alkanoyl, their salts and their tautomeric forms. 3. pyridazinones of general formula I according to claim 1, wherein R is a halogen atom, in particular chlorine, a lower alkyl group, in particular methyl or also the cyano group and Z has the meaning of hydrogen or lower alkanoyl, in particular acetyl, and their tautomeric forms. 4. 6- (3-cyano-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) pyridazinone and its tautomeric forms. 5. 6- (3-chloro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) pyridazinone and its tautomeric forms. 6. 6- (3-nitro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) pyridazinone and its tautomeric forms. 7. 6- (3-Cyano-4-morpholino-phenyl) -5-acetoxymethyl-4,5-dihydro-3 (2H) pyridazinone and its tautomeric forms. 8. Pharmaceutical preparations containing one of the compounds of claim 1. 9. The compounds of claim 1 for use in a method for the therapeutic treatment of the human and animal body. 10. The compounds of claim 1 for use as an antithrombotic agent. 11. The use of compounds of claim 1 for the manufacture of pharmaceutical preparations. 12. Process for the preparation of compounds of general formula I.

wherein R is a halogen atom; a lower alkyl, lower alkoxy, nitro, hydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl or the trifluoromethyl group, and Z represents hydrogen or an acyl group, their salts and their tautomeric forms, - characterized in that one a) a ketocarboxylic acid of the formula II

or reacting a reactive derivative of such a ketocarboxylic acid, in which R and Z have the meaning given above, with hydrazine, or b) a compound of formula III

wherein R and Z have the meanings given under the formula I, and Y is a group which can be split off together with hydrogen, is reacted with morpholine, or c) a compound of formula IV

with a diethyl ether derivative of formula V

wherein X is a group which can be split off together with hydrogen and R and Z have the meanings given above, or d) in a compound of formula VI

wherein X1 ^{⊝ represents} an anion of a mineral ^acid , in the presence of copper or a copper-I salt, introduces a halogen atom or the cyano group as R, or e) a compound of formula VII

halogenated, or f) a compound of formula VIII

in which R 'has the meaning of R or denotes an easily solvolysable or hydrogenolyzable ether group or acyloxy group and -OZ' denotes an easily solvolysable or hydrogenolyzable ether or acyloxy group, solvolysed or hydrogenolysed and / or, if desired, a compound of formula I obtained , in which R is a carboxyl group converted into a salt, and / or a salt of the compound of the formula I obtained is converted into a compound of the formula I in which R is a free carboxy group. 13. The procedures described in Examples 1-3. 14. The compounds obtainable by the processes of claim 12. Claims for the contracting state AT 1. Process for the preparation of pyridazinones of the formula I.

wherein R represents a halogen atom, a lower alkyl, lower alkoxy, the nitro, hydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl or the trifluoromethyl group, and Z represents hydrogen or an acyl group, their salts and their tautomeric forms, characterized in that one a) a ketocarboxylic acid of the formula II

or reacting a reactive derivative of such a ketocarboxylic acid, in which R and Z have the meaning given above, with hydrazine, or b) a compound of formula III

wherein R and Z have the meanings given under formula I, and Y represents a group which can be split off together with hydrogen, is reacted with morpholine, or c) a compound of formula IV

with a diethyl ether derivative of formula V

wherein X denotes a group which can be split off together with hydrogen and R and Z have the meanings given above, or d) in a compound of formula VI

wherein X ₁ ^{⊖ represents} an anion of a mineral ^acid , in the presence of copper or a Rupfer-I salt introduces a halogen atom or the cyano group as R, or e) a compound of formula VII

halogenated, or f) a compound of formula VIII

in which R 'has the meaning of R or denotes an easily solvolysable or hydrogenolyzable ether group or acyloxy group and -OZ' denotes an easily solvolysable or hydrogenolyzable ether or acyloxy group, solvolyses or hydrogenolyses and / or, if desired, a compound of formula I obtained , in which R denotes a carboxyl group is converted into a salt, and / or a salt of the compound of the formula I obtained is converted into a compound of the formula I in which R denotes a free carboxy group. 2. The method according to claim 1, characterized in that compounds of the general formula I given in claim 1, wherein R is a halogen atom, the cyano, hydroxyl, carboxy, lower alkyl, lower alkoxy or trifluoromethyl group and Z is the Significance of hydrogen or Niederalkanoyl has, their salts and their tautomeric forms. 3. The method according to claim 1, characterized in that compounds of the general formula I given in claim 1, wherein R is a halogen atom, in particular chlorine, a lower alkyl group, in particular methyl or also the cyano group and Z has the meaning of hydrogen or lower alkanoyl , especially acetyl, and their tautomeric forms. 4. The method according to claim 1, characterized in that 6- (3-cyano-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone and its tautomeric forms. 5. The method according to claim 1, characterized in that 6- (3-cyano-4-morpholino-phenyl) -5-acetoxymethyl-4,5-dihydro-3 (2H) -pyridazinone and its tautomeric forms. 6. The method according to claim 1, characterized in that 6- (3-chloro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone and its tautomeric forms. 7. The method according to claim 1, characterized in that 6- (3-nitro-4-morpholino-phenyl) -5-hydroxymethyl-4,5-dihydro-3 (2H) -pyridazinone and its tautomeric forms.